Prostate cancer is the most commonly diagnosed nonskin malignancy in males from developed countries. It is estimated that one in six males will be diagnosed with prostate cancer (PCa) in their lifetime. The diagnosis of PCa has greatly improved following the use of serum-based markers such as the prostate-specific antigen (PSA). However, the use of tumor-associated markers offers alternative strategies in disease management and may prove useful for in vivo tumor imaging purposes and further development of targeted therapies.
Identification of the prostate specific membrane antigen (PSMA) marker, a tumor associated marker, has generated interest for both applications. PSMA is a glycoprotein highly restricted to prostate secretory epithelial cell membranes. Its expression has been correlated with tumor aggressiveness. Various immunohistological studies have demonstrated increased PSMA levels in virtually all cases of prostatic carcinoma compared to those levels in benign prostate epithelial cells. Intense PSMA staining is found in all stages of the disease, including prostatic intraepithelial neoplasia, late stage androgen-independent prostate cancer and secondary prostate tumors localized to lymph nodes, bone, soft tissue, and lungs. PSMA was originally identified as the molecule recognized by 7E11, a monoclonal antibody (MAb) reactive to the prostate cancer cell line LNCaP. It was subsequently cloned from these cells as a 2.65 kb cDNA encoding a 750 amino acid cell surface type II integral membrane glycoprotein of 100 kDa. PSMA forms a noncovalent homodimer that possesses glutamate carboxypeptidase activity based on its ability to process the neuropeptide N-acetylaspartylglutamate and glutamate-conjugated folate derivatives. Although the precise biological role played by PSMA in disease pathogenesis remains elusive, its overexpression in PCa might potentially be associated with the growth balance of the prostate gland. Indeed, recent evidence suggests that PSMA performs multiple physiological functions related to cell survival and migration.
Antibody-based therapeutics have emerged as important components of therapies for an increasing number of human malignancies in such fields as oncology, inflammatory and infectious diseases. In most cases, the basis of the therapeutic function is the high degree of specificity and affinity the antibody-based drug has for its target antigen. Arming monoclonal antibodies with drugs, toxins, or radionuclides is yet another strategy by which mAbs may induce therapeutic effect. By combining the exquisite targeting specificity of antibody with the tumor killing power of toxic effector molecules, immunoconjugates permit sensitive discrimination between target and normal tissue thereby resulting in fewer side effects than most conventional chemotherapeutic drugs.
Given the physical properties of PSMA and its expression pattern in relation to disease progression, its large extracellular domain provides an excellent target in the development of ligands for diagnostic and therapeutic intervention. The first PSMA-specific MAb reported, 7E11, was subsequently developed and commercialized as a diagnostic agent for tumor imaging (ProstaScint, Cytogen, Princeton, N.J.). However, this antibody recognizes an intracellular epitope of PSMA which limits its usefulness as an imaging agent for the detection of PSMA. More recently, MAbs such as J591 that recognize the extracellular portion of PSMA were developed, however such antibodies have uncharacterized epitope specificities. The development of anti-PSMA antibodies with diagnostic and/or therapeutic activity is needed. The present invention seeks to meet these and other needs.